We are studying T cell antigen receptors (TCR) with the purpose of more fully understanding the requirements for their activation in an immune response. The two broad classes of TCR, alpha/beta TCR and gamma/delta TCR, are both under investigation. Our goal is to analyze these proteins biochemically and structurally. To do so requires that we produce sufficient amounts of protein for study and that we characterize the recombinant proteins for their appropriate functionality. Further study of their binding to ligands and of their three- dimensional structure by X-ray crystallography should lead to insights as to how these proteins function in the immune system. Unlike alpha/beta T cell receptors which recognize peptide antigens bound to major histocompatibility complex molecules, gamma/delta TCRs can directly recognize antigens in the form of intact proteins or non-peptidic compounds. About 5% of all primate peripheral blood T cells bear gamma/delta TCRs, most of which recognize a number of non-peptidic phosphorylated antigens. We have determined the structure of a human gamma/delta TCR isolated from a T cell clone that is activated by these phosphoantigens. We are now studying the binding of non-peptidic phosphorylated antigens to the gamma/delta TCR using several crystallographic, biochemical, and biophysical techniques.